Process for the preparation of enantiomerically enriched 3-aminopiperidine

ABSTRACT

The present invention relates to a process for the preparation of enantiomerically enriched 3-aminopiperidine, and in particular of its R-enantiomer (R)-3-aminopiperidine. The invention also relates to an enantiomerically enriched intermediate of said process and to specific acid-addition salts of 3-aminopiperidine (hereinafter also APIP) that are useful for obtaining a single enantiomer of APIP, and to crystalline (R)-3-aminopiperidine-dihydrochloride-monohydrate and crystalline (S)-3-aminopiperidine-di-hydrochloride-monohydrate.

RELATED APPLICATION(S)

This application claims priority to European Application No. 13156030.2,filed Feb. 20, 2013.

The present invention relates to a process for the preparation ofenantiomerically enriched 3-aminopiperidine, and in particular of itsR-enantiomer (R)-3-aminopiperidine. The invention also relates to anenantiomerically enriched intermediate of said process and to specificacid-addition salts of 3-aminopiperidine (hereinafter also APIP) thatare useful for obtaining a single enantiomer of APIP, and to crystalline(R)-3-aminopiperidine-dihydrochloride-monohydrate and crystalline(S)-3-aminopiperidine-dihydrochloride-monohydrate.

BACKGROUND OF THE INVENTION

Both (R)- and (S)-3-aminopiperidine are valuable building blocks for thepreparation of bioactive compounds, such as antagonistic ligands ofreceptors in the central nervous system. (R)-3-aminopiperidine is alsoknown to be a key intermediate for the synthesis of dipeptidylpeptidase-4 inhibitors, such as alogliptin and linagliptin, and aprotein kinase inhibitor.

Several approaches for the enantioselective preparation of(R)-3-aminopiperidine have been described in the art that rely on thecyclization of α-amino acids or their derivatives, such as D-ornithineand derivatized D-glutamic acid, or on the hydrogenation of usuallyderivatized 3-aminopyridine followed by enantiomeric separation. Theseapproaches typically require expensive starting materials, a largenumber of synthesis steps, or expensive hydrogenation catalystsincluding platinum group metals, and are therefore not suitable forindustrial scale syntheses.

Alternatively, 3-aminopiperidine derivatives have been prepared in theprior art, either in the form of the R-enantiomer or in the form of theracemate, via a Curtius or Hofmann rearrangement of N-protectednipecotic acid (piperidine-3-carboxylic acid) derivatives. Particularexamples of this approach are the following:

US 2001/0056090 describes the synthesis of(R)-3-benzyloxycarbonylamino-1-tert-butyloxycarbonyl-piperidine byreacting N-tert-butyloxycarbonyl-protected (R)-nipecotic acid withisobutylchoroformate/triethylamine and then sodium azide. The obtainedacyl azide is then subjected to a Curtius rearrangement yielding thecorresponding isocyanate which is heated with benzyl alcohol to give thetitle compound.

Jean et al., Tetrahedron Letters 2001, 42, 5645-5649, disclose Curtiusrearrangement of N-benzyl protected nipecotic acid hydrazide in thepresence of sodium nitrite yielding 1-benzyl-3-aminopiperidine.

US 2010/0105917 discloses Hofmann rearrangement of (R)-nipecotic acidamide, which is N-protected with a tert-butyloxycarbonyl group or anoptionally substituted benzoyl group, to the correspondingly N-protected(R)-3-aminopiperidine.

The additional steps for introducing and removing an N-protecting groupthat are required in the aforementioned 3-aminopiperidine syntheticroutes are particularly disadvantageous for the preparation of(R)-3-aminopiperidine on an industrial scale.

Furthermore, JP 2011/012032 discloses methods for the enantiomericresolution of racemic or insufficiently enantiomerically enriched3-aminopiperidine, which methods are based on the crystallization of thediastereomeric acid addition salts of one of the enantiomers. Accordingto this document (R)-3-aminopiperidine can be obtained from the racemateby crystallizing it as its acid addition salt that is formed in thepresence of 2 equivalents of (R)-2-methoxy-2-phenylacetic acid or 2equivalents of N-(para-toluenesulfonyl)-L-phenylalanine. Unfortunately,both options are unsatisfactory as (R)-2-methoxy-2-phonylacetic acid isextremely expensive and, regarding the latter case, virtually noresolution could be obtained withN-(para-toluenesulfonyl)-L-phenylalanine, in the hands of the inventorsof the present invention. Likewise, the use ofN-(para-toluenesulfonyl)-L-phenylalanine in the dielectricallycontrolled resolution of 3-aminopiperidine via the diastereomeric acidaddition salt, as described by Sakurai et al., Tetrahedron Asymmetry2012 23, 221-224, resulted in either poor yield or insufficientenantomeric excess.

WO 2007/075630 discloses the chiral resolution of 3-aminopiperidine viadiastereomeric acid addition salts formed with dibenzoyl-L-tartaricacid, di(ortho-tolyl)-L-tartaric acid and N-acetyl-phenylalanine.However, all these chiral acids are instable and lead to only modestresolution at the most.

Therefore, there is still a strong need for providing a process forpreparing APIP, that overcomes the disadvantages of the prior art. Inaddition, in case such a process, or another process for preparing APIP,yields racemic or insufficiently enantiomerically enriched APIP, thereis also a need for a process enabling enantiomeric enrichment of APIP,in particular of (R)-APIP, which does not suffer the deficiencies of theprior art.

SUMMARY OF THE INVENTION

Surprisingly, it has been found that the first object is solved by aprocess for preparing 3-aminopiperidine that does not requireintermediate protection of the secondary amine group of the piperidinemoiety.

Therefore, according to a first aspect the present invention relates toa process for preparing 3-aminopiperidine which comprises the followingsteps:

-   a) providing piperidine-3-carboxylic acid hydrazide, and-   b) transforming piperidine-3-carboxylic acid hydrazide into the    piperidine-3-carbonyl azide and-   c) reacting piperidine-3-carbonyl azide in the presence of water and    an acid.

The reaction in step c) is a Curtius rearrangement which in generalinvolves elimination of nitrogen gas from an acyl azide andrearrangement to the corresponding isocyanate. Hydrolysis anddecarboxylation of the isocyanate then yields the corresponding amine.Thus, step c) affords the intended 3-aminopiperidine.

The Curtius rearrangement typically proceeds with retention of theconfiguration at the carbon atom that is attached to the carbonyl group.Accordingly the configuration at the chiral center of thepiperidine-3-carboxylic acid hydrazide that is provided in step a) ofthe inventive process is identical with the one of the 3-aminopiperidineobtained in step c) of the process. As a consequence, the process of theinvention results in a racemic, a (R)-configurated or a (S)-configurated3-aminopiperidine in case a racemic, a (R)-configurated or a(S)-configurated piperidine-3-carboxylic acid hydrazide, respectively,is introduced into step b) of the process.

The aforementioned process of the invention is associated with severaladvantages. In particular, it allows the preparation of3-aminopiperidine in a short and high yielding synthetic route that caneasily be performed on an industrial scale.

It has also surprisingly been found that the second object is solved byfractional crystallization of acid addition salts of APIP with aN-modified alanine derivative, in particular the chiral carboxylic acidA which is a L-alanine or D-alanine derivative of the formula A:

wherein X is S(O)₂, C(O) or NHC(O), k is 0, 1, 2, 3, 4 or 5 and R is CN,NO₂, C₁-C₂-alkyl, C₁-C₂-alkoxy or halogen, or two adjacent variables Rmay together represent an optionally substituted butadien-1,4-diylradical. According to a preferred embodiment X is S(O)₂ or NHC(O), k is0, 1, 2 or 3 and R is C₁-C₂-alkyl, C₁-C₂-alkoxy or halogen.

Therefore, according to a second aspect the present invention relates toa process for the enantiomeric enrichment of APIP, the processcomprising the fractional crystallization of APIP in the form of itsacid addition salt with a chiral carboxylic acid A as described herein,where the chiral carboxylic acid is enantiomerically enriched withregard to one of its enantiomers, from a solution, emulsion orsuspension containing a mixture of the enantiomers of APIP and thechiral carboxylic acid A, whereby the acid addition salt of APIP withthe chiral carboxylic acid A is obtained, which is enantiomericallyenriched with regard to the desired enantiomer of APIP.

The invention also relates to the novel acid addition salts of APIP withsaid chiral carboxylic acid A, in particular to enantiomericallyenriched or enantiomerically pure acid addition salts of APIP with thecarboxylic acid of the formula A. A particular embodiment of theinvention relates to the acid addition salts of APIP withN-(para-toluenesulfonyl)-L-alanine,N-(para-chlorophenylsulfonyl)-L-alanine, N-(phenylsulfonyl)-L-alanine,N-(phenylcarbamoyl)-D-alanine or N-(4-chlorophenylcarbamoyl)-D-alanine,in particular those that are enriched with regard to the R-enantiomer ofAPIP. Another particular embodiment of the invention relates to the acidaddition salt of APIP with N-(para-toluenesulfonyl)-D-alanine,N-(para-chlorophenylsulfonyl)-D-alanine, N-(phenylsulfonyl)-D-alanine,N-(phenylcarbamoyl)-L-alanine or N-(4-chlorophenyl-carbamoyl)-L-alanine,in particular those that are enriched with regard to the S-enantiomer ofAPIP.

In this context, enantiomeric enrichment means that the enantiomericexcess (ee) with regard to one enantiomer of APIP in the acid additionsalt is at least 50%, frequently at least 60%, in particular at least70% or at least 80%. Particular embodiments relate to enantiomericallyenriched acid addition salts of APIP with the carboxylic acid of theformula A, wherein the enantiomeric excess (ee) with regard to oneenantiomer of APIP in the acid addition salt is 70% or higher, inparticular 80% or higher or even 90% ee or higher such as >95% eeor >98% ee.

The use of the acid addition salt of APIP with the carboxylic acid Aprovides good crystallization yields and satisfactory enantiomericenrichment generally exceeding 80:20 (ee=60%), frequently at least 85:15(ee=70%), in particular at least 90:10 (ee=80%) or at least 95:5(ee=90%), without using expensive chiral auxiliaries. Satisfactoryenrichment can be obtained without prior enrichment of the APIP to beresolved. The crystallization of the acid-addition salt of APIPaccording to the invention can also be carried out in an aqueoussolution, suspension or emulsion, which renders the process moreeconomical, environment-friendly and less risky, since the use ofexpensive or hazardous organic solvents can be reduced or avoided.

The invention also relates to crystalline(R)-3-aminopiperidine-dihydrochloride-monohydrate, which is obtainableby using either one or both of the two aforementioned inventiveprocesses. The enantiomeric enrichment of the R-enantiomer is preferablyat least 85:15 (ee=70%), in particular at least 90:10 (ee=80%) or atleast 95:5 (ee=90%).

The invention also relates to crystalline(S)-3-aminopiperidine-dihydrochloride-monohydrate, which is obtainableby using either one or both of the two aforementioned inventiveprocesses. The enantiomeric enrichment of the S-enantiomer is preferablyat least 85:15 (ee=70%), in particular at least 90:10 (ee=80%) or atleast 95:5 (ee=90%).

In a further aspect, the invention relates to non-racemicpiperidine-3-carboxylic acid hydrazide, which is enantiomericallyenriched either with regard to its R-enantiomer or with regard to its3-enantiomer, and the acid addition salts and hydrates thereof. Theenantiomeric enrichment is preferably at least 85:15 (ee=70%), inparticular at least 90:10 (ee=80%) or at least 95:5 (ee=90%).

In a further aspect, the invention relates to piperidine-3-carbonylazide, in particular to non-racemic piperidine-3-carbonyl azide, whichis enantiomerically enriched either with regard to its R-enantiomer orwith regard to its S-enantiomer. The enantiomeric enrichment ispreferably at least 85:15 (ee=70%), in particular at least 90:10(ee=80%) or at least 95:5 (ee=90%).

DETAILED DESCRIPTION OF THE INVENTION

In the context of the present invention, the terms used generically aredefined as follows:

The term “halogen” as used herein includes e.g. fluorine, chlorine,bromine or iodine, with particular preference given to chlorine.

The term “C₁-C₈-alkyl” as used herein includes linear or branched alkylgroups having from 1 to 8, in particular 1 or 4 carbon atoms(═C₁-C₄-alkyl), such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, 1,1-dimethylethyl (=tert.-butyl), n-pentyl, n-hexyl andn-octyl.

The term “C₁-C₄-alkoxy” as used herein includes linear or branchedalkoxy radicals preferably from 1 to 4, in particular 1 or 2 carbonatoms (═C₁-C₂-alkoxy), such as methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, isobutoxy and 1,1-dimethylethyloxy.

The term “phenyl-C₁-C₄-alkyl” as used herein includes linear or branchedalkyl groups having 1 to 4, in particular 1 or 2 carbon atoms, whereinone hydrogen atom is replaced by a phenyl group, such as benzyl.

The process of the invention for preparing 3-aminopiperidine, hereinalso called process A, comprises the following steps:

-   a) providing piperidine-3-carboxylic acid hydrazide, e.g. by    reacting a derivative of piperidine-3-carboxylic acid (nipecotic    acid), such as nipecotic acid halide or an alkyl ester or benzyl    ester of nipecotic acid, with hydrazine, and-   b) transforming piperidine-3-carboxylic acid hydrazide into the    piperidine-3-carbonyl azide, e.g. by reacting the hydrazide with an    inorganic or organic nitrite compound, and-   c) reacting piperidine-3-carbonyl azide in the presence of water and    an acid, which typically yields 3-aminopiperidine via Curtius    rearrangement and subsequent hydrolysis.

Process A is suitable for providing APIP that is a racemic mixture ofboth enantiomers or is enriched in respect to the R- or theS-enantiomer. Process A is especially useful for generatingenantiomerically enriched APIP, such as in particular APIP that isenriched with regard to the R-enantiomer or the S-enantiomer.Preferably, in order to obtain APIP in enantiomerically enriched form,either an enantiomerically enriched derivative of nipecotic acid, suchas the C₁-C₄-alkyl ester or benzyl ester of (R)-nipecotic acid or theC₁-C₄-alkyl ester or benzyl ester of (S)-nipecotic acid, in particularthe C₁-C₄-alkyl ester, especially the ethyl ester of (R)- or(S)-nipecotic acid, is converted in step a) into piperidine-3-carboxylicacid hydrazide or, in the alternative, the 3-aminopiperidine obtained instep c) of the process A is subjected to an enantiomeric enrichmentprocess.

The reactions of the invention as described hereinafter are performed inreaction vessels customary for such reactions, the reaction beingcarried out in a continuous, semicontinuous or batchwise manner. Ingeneral, the particular reactions will be carried out under atmosphericpressure. The reactions may, however, also be carried out under reducedor elevated pressure.

The provision of piperidine-3-carboxylic acid hydrazide in step a) ofprocess A of the invention may be accomplished by any method known inthe art for preparing carboxylic acid hydrazides. Preferably, however,said provision is effected by reacting either a piperidine-3-carboxylicacid halide, such as the acid bromide or acid chloride and in particularthe acid chloride, or a C₁-C₄-alkyl ester or benzyl ester ofpiperidine-3-carboxylic acid with hydrazine.

In process A according to the invention, hydrazine is understood to meanthe hydrazine reactant, either as the anhydrous liquid, as hydrazinehydrate comprising about one molecule water per one molecule hydrazine(N₂H₄.H₂O) or as a solution, in particular an aqueous solution,preferably having a water content of 35 to 70% (w/w). In addition,hydrazine can also be understood to mean the hydrazine reactant as asalt of hydrazine, such as for example hydrazine acetate, hydrazinemonohydrochloride, hydrazine dihydrochloride, hydrazine hemisulfate,hydrazine sulphate. Preference is given to using the hydrazine hydrate.

According to a preferred embodiment step a) of process A is accomplishedby the reaction of a C₁-C₄-alkyl ester or benzyl ester (herein alsocalled AEPC), in particular a C₁-C₄-alkyl ester ofpiperidine-3-carboxylic acid, especially the ethyl ester ofpiperidine-3-carboxylic acid, with hydrazine, preferably in the form ofits hydrate. AEPC may be employed in the form of a racemic mixture or inthe form of a non-racemic mixture, such as in particular a mixture thatis enantiomerically enriched with regard to the R-enantiomer of AEPC ora mixture that is enantiomerically enriched with regard to theS-enantiomer of AEPC.

The reaction may be carried out with or without an explicit solvent.Suitable solvent here are water, polar organic solvents that are inertunder the given reaction conditions, or a mixture of such a polarorganic solvent with water. Appropriate polar organic solvents in thiscontext are for instance C₁-C₄-alkanols, e.g. methanol, ethanol,n-propanol, isopropanol and butanol, ethers, e.g. aliphaticC₄-C₁₀-ethers having 1, 2, 3, or 4 oxygen atoms and alicyclicC₄-C₆-ethers, such as ethylene glycol dimethyl ether, diethylene glycoldimethyl ether, triethylene glycol dimethyl ether, diethyl ether,tetrahydrofuran and 1,4-dioxane, and mixtures thereof. The reaction mayalso be carried out in a biphasic solvent mixture comprising an aqueousphase and an aromatic solvent such as for example toluene or xylene.Preferably, however, the reaction is carried out in the absence of anyexplicit solvent or in a biphasic solvent mixture comprising toluene orxylene.

The aforementioned reaction of an alkyl or benzyl ester ofpiperidine-3-carboxylic acid with hydrazine is typically performed at atemperature in the range from 20 to 150° C., preferably in the rangefrom 30 to 110° C., in particular in the range from 40 to 90° C. andspecifically in the range from 50 to 80° C.

In relation to the alkyl or benzyl ester of piperidine-3-carboxylic acidthe hydrazine is preferably used at least in equimolar amounts and morepreferably in amounts of 1 to 2.0 moles per 1 mol of the ester. In casethe reaction is carried out in the absence of any explicit solvent, thehydrazine is used in particular in amounts of 1 to 1.2 moles per 1 molof the ester and specifically in amounts of 1.05 to 1.15 moles per 1 molof the ester. In case the reaction is carried out in a biphasic solventmixture, the hydrazine is used in particular in amounts of 1.3 to 1.8moles per 1 mol of the ester and specifically in amounts of 1.4 to 1.6moles per 1 mol of the ester.

According to a preferred embodiment of the inventionpiperidine-3-carboxylic acid hydrazide is prepared by reacting asolution of ethyl ester of piperidine-3-carboxylic acid in toluene orxylene with 1.4 to 1.6 molar equivalents of hydrazine hydrate at atemperature of 50 to 80° C.

The reaction mixture obtained in step a) of process A may be subjectedto a work-up procedure or may be introduced directly Into a followingsynthesis step either without any prior work-up or after removal oforganic solvent, if present, and of a remaining excess of hydrazine thatmay be included in the mixture.

The work-up of the reaction mixture obtained in step a) of process A andthe isolation of piperidine-3-carboxylic acid hydrazide can be effectedin a customary manner. Preferably the reaction mixture is initiallydiluted with water or an aqueous solution of a polar organic solvent,and in particular with water. The piperidine-3-carboxylic acid hydrazidecan then be crystallized from the dilution in the form of its additionsalt by adding an acid that is preferably selected from mineral acidssuch as sulphuric acid, hydrochloric acid or hydrobromic acid, like inparticular concentrated hydrochloric acid. The acid is preferably addedslowly to the dilution after it has been cooled down usually to atemperature in the range of 0 to 50° C., preferably of 10 to 30° C. andin particular of 15 to 25° C., e.g. to ambient temperature. Theconcentrated hydrochloric acid is usually added in amounts of about 1molar equivalent, such as 0.9 to 1.2 and in particular 0.95 to 1.1 molarequivalents, or of about 2 molar equivalents, such as 1.8 to 2.4 and inparticular 1.9 to 2.2 molar equivalents, based in each case on theamount of the alkyl ester of piperidine-3-carboxylic acid used.Depending on whether about 1 molar equivalent or about 2 molarequivalents of hydrochloric acid are added, the piperidine-3-carboxylicacid hydrazide can be isolated in its monohydrochloride form or itsdihydrochloride form. After completion of the crystallization theobtained crystals of the addition salt are isolated by filtration. Theisolated crystals are usually washed with cold water and optionallyafterwards with a polar organic solvent such as an alkanol, e.g.isopropanol and optionally thereafter with a nonpolar organic solventsuch as a hydrocarbon solvent, e.g. pentane, hexane or cyclohexane.Further amounts of the addition salt can typically be obtained from themother liquor via evaporation of the solvent and recrystallization fromwater or another suitable solvent or solvent mixture. Thepiperidine-3-carboxylic acid hydrazide is preferably isolated in theform of its monohydrochloride addition salt, which is obtained by addingabout 1 molar equivalent of hydrochloric acid to the diluted reactionmixture, as described above.

Preferably the reaction mixture obtained in step a) of process A isintroduced directly into a following synthesis step either without anyprior work-up measures or after removal of organic solvent, if present,and of a remaining excess of hydrazine that may be included in themixture. According to a particularly preferred embodiment of theinvention reaction mixture obtained in step a) is introduced into afollowing synthesis step after organic solvent, if present, and of aremaining excess of hydrazine has been removed from the mixture. Anexcess of hydrazine is typically removed by azeotropic distillation.

According to one embodiment of the invention piperidine-3-carboxylicacid hydrazide is provided in step a) as a racemic mixture of itsenantiomers, including the acid addition salts and the hydrates thereof.Such a racemic mixture is preferably prepared by reacting a racemicAEPC, in particular racemic ethyl ester of piperidine-3-carboxylic acid,with hydrazine and in particular with hydrazine hydrate.

According to a particular embodiment of the inventionpiperidine-3-carboxylic acid hydrazide is provided in step a) as anon-racemic mixture of its enantiomers, where the mixture isenantiomerically enriched with regard to one of its enantiomers, inparticular with regard to its R-enantiomer. Said non-racemic mixture ofthe enantiomers of piperidine-3-carboxylic acid hydrazide is herein alsocalled enantiomerically enriched piperidine-3-carboxylic acid hydrazide.In this context enantiomeric enrichment means that the enantiomericexcess (ee) with regard to one enantiomer of piperidine-3-carboxylicacid hydrazide in the non-racemic mixture is at least 50%, frequently atleast 60%, in particular at least 70% or at least 80%. Preferredembodiments of the invention relate to enantiomerically enrichednon-racemic mixtures of piperidine-3-carboxylic acid hydrazide, whereinthe enantiomeric excess (ee) with regard to one enantiomer ofpiperidine-3-carboxylic acid hydrazide in the acid addition salt is 90%ee or higher such as >95% ee or >98% ee.

A particular embodiment of the invention relates topiperidine-3-carboxylic acid hydrazide, which is enantiomericallyenriched with regard to one of its enantiomers, in particular withregard to its R-enantiomer or to an acid addition salt thereof, such asa sulphate, hydrogensulfate, hydrochloride or hydrobromide, or a hydratethereof.

Said enantiomerically enriched piperidine-3-carboxylic acid hydrazide ispreferably prepared in step a) by reacting AEPC, in particular ethylester of piperidine-3-carboxylic acid, which is enantiomericallyenriched with regard to one of its enantiomers, in particular itsR-enantiomer, with hydrazine and in particular with hydrazine hydrate.

Enantiomerically enriched AEPC, in turn, can be obtained by any methodknown in the art for this or a similar purpose, for example byasymmetric synthesis, by synthesis starting from a chiral precursor,such as enantiomerically enriched piperidine-3-carboxylic acid, or byenantiomeric enrichment of a mixture of the AEPC enantiomers.

Enantiomeric enrichment of AEPC can be accomplished by customarymethods, e.g. by chiral chromatography or by separation of thediastereomers that can be generated by derivatizing AEPC with a chiralresolving agent. Preferred chiral resolving agents in this context arechiral acids capable of forming diastereomeric acid addition salts thatcan be enriched regarding one enantiomer of the C₁-C₄-alkylester orbenzyl ester of piperidine-3-carboxylic acid, for example by fractionalcrystallization.

According to a preferred embodiment of the invention step a) of processA comprises subjecting racemic AEPC, in particular the racemic ethylester of piperidine-3-carboxylic acid, to enantiomeric enrichment byfractional crystallization of an acid addition salt of AEPC with achiral acid. However, it is also possible to enrich non-racemic mixturesof the AEPC enantiomers in this manner. This enantiomeric enrichment canbe used to enrich the R-enantiomer or the S-enantiomer of the AEPC, andis preferably used to enrich the R-enantiomer. Preferred chiral acids inthis respect or those known in the art, such as tartaric acid, asdescribed for example in U.S. Pat. No. 5,220,016 and in WO 00/56730, ormandelic acid or dibenzoyl tartaric acid as described in EP1341762, orethers of 2-hydroxy-propionic acid as described in U.S. Pat. No.6,340,762. Enantiomeric enrichment of the R-enantiomer of AEPC ispreferably achieved by crystallization of the acid addition salt of AEPCwith one of the following acids: L(+) tartaric acid or D-mandelic acid.Enantiomeric enrichment of the S-enantiomer of AEPC is preferablyachieved by crystallization of the acid addition salt of AEPC with oneof the following acids: D(−) tartaric acid or L-mandelic acid.

As outlined above, the fractional crystallization of AEPC with a chiralacid results in crystals of acid addition salts of AEPC which areenantiomerically enriched with regard to (R)- or (S)-AEPC. Thus, themother liquor obtained in said crystallizations is depleted with regardto this respective enantiomer of AEPC and therefore contains an excessof the opposite enantiomer of AEPC. For example, the mother liquorobtained from the crystallization of (R)-AEPC acid addition salts isenriched with regard to (S)-AEPC. In order to avoid loss of yield theAPEC of said mother liquor may be subjected to a racemization. In thisway, subsequent to the racemization, an additional amount of the desiredenantiomer of APEC, such as (R)-AEPC, can be prepared by means ofenantiomeric enrichment, for example according to the methods involvingfractional crystallization mentioned above. Racemization of non-racemicAEPC is usually accomplished by treating AEPC with a base according toknown procedures that are described for example in WO02/068391. Suitablemethods include e.g. treatment with catalytic amounts of sodiumethoxylate as base.

The acid addition salts of AEPC with a chiral acid obtained by themethods for enantiomeric enrichment of the preceding embodiment can betransformed into the free base, i.e. free AEPC, according to well-knowntechniques. Typically, for preparing the free base the acid additionsalt of AEPC is treated either with a diluted aqueous base, such as anaqueous solution of an alkali metal carbonate, alkali metal hydrogencarbonate or alkali metal hydroxide such as sodium carbonate, potassiumcarbonate, sodium hydrogen carbonate, sodium hydroxide, calciumhydroxide or potassium hydroxide, or with a basic ion exchange resin.The free base may be extracted from the thus obtained mixture by asuitable method, such as extraction with an organic solvent. Theaddition of base is preferably conducted under cooling. It is furtherpreferred to use a concentrated aqueous solution of a base.

In step b) of the process A the piperidine-3-carboxylic acid hydrazideobtained in step a) is converted into piperidine-3-carbonyl azide. Thereaction is usually carried out by contacting thepiperidine-3-carboxylic acid hydrazide with a nitrite under acidicconditions in a solvent using suitable reaction conditions. Thepiperidine-3-carboxylic acid hydrazide may be used as its free base oras an acid addition salt thereof or a hydrate thereof, in particular asthe free base or as the acid addition salt thereof with a mineral acidsuch as hydrochloric acid, sulphuric acid or hydrobromic acid.

Piperidine-3-carboxylic acid hydrazide is typically employed in step b)as is, i.e. as the free base, or as its acid addition salt, inparticular as its monohydrochloride or as its dihydrochloride, and ispreferably employed as the free base.

In process A according to the invention, nitrite is understood to meanboth inorganic and organic nitrites, including nitrous acid, one of itssalts, and organic nitrite or a mixture thereof. Suitable salts ofnitrous acid are in particular its alkali metal salts, e.g. sodiumnitrite, potassium nitrite or lithium nitrite, and its alkali earthmetal salts, such as calcium nitrite or barium nitrite. Preferred saltshere are alkali metal salts, in particular sodium nitrite and potassiumnitrite. The term “organic nitrite” in this context means astraight-chain or branched C₁-C₈-alkyl nitrite, such as methyl nitrite,ethyl nitrite, n-propyl nitrite, isopropyl nitrite, n-butyl nitrite,isobutyl nitrite, tert-butyl nitrite, n-pentyl nitrite, isopentylnitrite (isoamyl nitrite), neopentyl nitrite (2,2-dimethylpropylnitrite), n-hexyl nitrite and 2-ethylhexyl nitrite, a C₅-C₈-cycloalkylnitrite, such as cyclohexyl nitrite, a phenyl-C₁-C₄-alkyl nitrite, suchas benzyl nitrite, or a mixture thereof. Preferred organic nitrites foruse in process A are n-butyl nitrite, isobutyl nitrite, tert-butylnitrite, n-pentyl nitrite, isopentyl nitrite and mixtures thereof, andparticular preference is given to tert-butyl nitrite, isopentyl nitriteand a mixture thereof.

According to a special embodiment of the invention the nitrite used inprocess A is isopentyl nitrite, butyl nitrite or sodium nitrite and inparticular isopentyl nitrite or butyl nitrite.

The nitrite is used in the conversion of step b) in an amount of usually1 to 2 molar equivalents, preferably 1 to 1.5 molar equivalents and inparticular 1.05 to 1.4 molar equivalents, based on the amount ofpiperidine-3-carboxylic acid hydrazide used.

Typically the conversion of step b) is carried out in the presence of 1to 4 molar equivalents, preferably 1.2 to 3 molar equivalents, morepreferably 1.5 to 2.5 molar equivalents and in particular 1.7 to 2.3molar equivalents of an acid, based on the amount ofpiperidine-3-carboxylic acid hydrazide used.

The amount of acid to be added to the reaction mixture depends on theforms in which the nitrite and the piperidine-3-carboxylic acidhydrazide are employed in the conversion of step b). For instance, ifnitrite is employed as nitrous acid it is generally advisable to reducethe amount of acid to be added by the corresponding number of molarequivalents. Likewise, if piperidine-3-carboxylic acid hydrazide isemployed as its acid addition salt, e.g. as its mono- ordihydrochloride, the amount of acid to be added should becorrespondingly reduced. Thus, if the dihydrochloride ofpiperidine-3-carboxylic acid hydrazide is used in step b) additionalacid is usually not required.

Suitable acids are in particular strong acids, such as hydrochloricacid, sulphuric acid or organic sulfonic acids, such as alkylsufonicacids or arylsulfonic acids. Preference is given here to hydrochloricacid.

Solvents that are suitable for the reaction in step b) include water andpolar organic solvents and mixtures thereof. Examples of suitable polarorganic solvents are in particular alcohols, such as C₁-C₅-alkanols,e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,tert.-butanol or n-pentanol, C₁-C₄-carboxylic acids, such as acetic acidor propionic acid, 5- and 6-membered lactones such as γ-butyrolactone,polyols and polyetherols, such as ethylene glycol, propylene glycol,glycerol, dimethoxyethane, ethylendlglycol orethylenglycolmonomethylether. Preferred polar organic solvents here areC₁-C₄-alkanols, in particular isopropanol, and C₁-C₃-carboxylic acids,in particular acetic acid. Preferred solvents for use in step b) of theinventive process A are water and mixtures of water with C₁-C₄-alkanols,such as isopropanol, or with C₁-C₃-carboxylic acids, such as aceticacid. Particular preference is given to water.

The total amount of solvent used in step b) of the process A accordingto the invention is usually in the range from 100 to 1000 g, preferablyin the range from 250 to 800 g and in particular in the range from 350to 700 g, based on 1 mol of piperidine-3-carboxylic acid hydrazide.

The piperidine-3-carboxylic acid hydrazide and the nitrite can inprinciple be contacted with one another in any desired sequence. Forexample, the piperidine-3-carboxylic acid hydrazide, if appropriatedissolved in a solvent or in dispersed form, can be initially chargedand admixed with the nitrite or, conversely, the nitrite, if appropriatedissolved in a solvent or in dispersed form, can be initially chargedand admixed with the piperidine-3-carboxylic acid hydrazide.Alternatively, these two components can also be added simultaneously tothe reaction vessel. If required, an acid can be added to the vesselbefore or after the addition of the piperidine-3-carboxylic acidhydrazide or else together with it.

It has been found to be appropriate to initially charge the reactionvessel with piperidine-3-carboxylic acid hydrazide (in the form of itsfree base or in the form of an acid addition salt thereof or a hydratethereof), preferably dissolved or dispersed in at least part of thesolvent, and then add the acid, if required, while keeping the reactionmixture at a temperature of about −10 to 10° C. and preferably of about−5 to 5°. Afterwards the nitrite is typically added either continuouslyor stepwise at a temperature of about −25 to 5° C. and preferably ofabout −18 to 0° C., depending on the reaction conditions of theindividual case. After the addition of the nitrite is completed thereaction mixture is allowed to warm up to temperature of −5 to 5° C.,preferably −3 to 3° C., and agitated for about 10 minutes to 4 hours andpreferably for about 20 minutes to 2 hours.

The work-up of the reaction mixture obtained from the conversion in stepb) and the isolation of the piperidine-3-carbonyl azide can, if desired,be effected in a customary manner, for example by removing the solvent,e.g. under reduced pressure, or by precipitation. Preferably, however,the reaction product obtained from the conversion in step b) issubjected, without preceding work-up, to the conversion in step c) ofthe process A according to the invention. To this end, the reactionmixture obtained after the completion of the conversion in step b) istypically introduced directly to the conversion in step c).

Thus, according to a particular preferred embodiment of the inventionsteps b) and c) of process A are performed without intermediateisolation of piperidine-3-carbonyl azide.

In step c) of the process A the piperidine-3-carbonyl azide obtained instep b) is converted Into 3-aminopiperidine (APIP). The reaction isusually carried out by heating piperidine-3-carbonyl azide in a solventI under hydrolytic conditions.

It has generally been found to be advantageous to initially provide asolution or dispersion of piperidine-3-carbonyl azide in a solvent Ithat is selected from the solvents mentioned above as suitable for theconversion in step b) and in particular from those mentioned there aspreferred. Piperidine-3-carbonyl azide is usually solved or dispersed in100 to 1000 g, preferably in 250 to 800 g and in particular in 350 to700 g of the solvent I, based on 1 mol of piperidine-3-carbonyl azide.

According to a preferred embodiment of the invention said solution ordispersion of piperidine-3-carbonyl azide is provided in the form of thereaction mixture obtained after the conversion in step b) of the processA, i.e. after completion of the reaction in step b) the reaction mixtureis used as said initial solution or dispersion of piperidine-3-carbonylazide in step c).

Typically, the initially provided solution or dispersion ofpiperidine-3-carbonyl azide is then added either continuously, stepwiseor in one portion, and preferably continuously or stepwise, to a solventII which has a temperature in the range of 50 to 150° C., preferably inthe range of 70 to 120° C. and in particular in the range of 75 to 100°C. Thereafter the reaction mixture is kept at about this temperature fora period of 2 minutes to 4 hours, preferably 5 minutes to 2 hours and inparticular 8 minutes to 1.5 hours, and afterwards cooled to aboutambient temperature.

Suitable solvents II are those mentioned above as suitable for theconversion in step b). Particular preference is given, however, to wateras solvent II.

The work-up of the reaction mixture obtained in step c) of the process Aand the isolation of APIP can be achieved by methods customary in theart, such as removal of the solvent, e.g. under reduced pressure,extraction of an aqueous solution of APIP with an non-water miscibleorganic solvent, precipitation, e.g. crystallization of3-aminopiperidine as its mono- or dihydrochloride, or a combination ofthese measures. Alternatively, the reaction mixture obtained from theconversion in step c) may be subjected, without any preceding work-upsteps, to a process for the enantiomeric enrichment of APIP, and inparticular one that is based on the fractional crystallization of APIPin the form of its addition salt with a chiral acid.

Preferably, for work-up, after the addition of 0.5 to 2.5 molarequivalents, and in particular 0.8 to 2.0 molar equivalents, ofhydrochloric acid, based on the amount of piperidine-3-carbonyl azideused, the reaction mixture is concentrated by removing at least a majorportion of the solvent. The remaining material may optionally be takenup in water, concentrated, taken up in an appropriate organic solvent,such as in particular isopropanol and concentrated again. The resultingresidue is dissolved, preferably with heating, in a relative smallamount of a polar organic solvent, such as in particular methanol. Tothe obtained solution, after cooling it to about ambient temperature,was gradually added a less polar organic solvent, such as in particularacetone or isopropanol, in amounts about 30 to 300% by weight, relativeto the amount of the aforementioned polar organic solvent. In case anenantiomerically enriched APIP has been synthesized before the additionof said less polar solvent the solution may optionally be seeded withthe corresponding crystalline hydrochloride. The thus obtainedprecipitate is optionally dried via azeotropic distillation underreduced pressure after adding for example isopropanol or a mixture ofisopropanol with methanol, and to the resulting suspension theaforementioned polar solvent, such as methanol, is added, optionallywith heating, and then the aforementioned less polar solvent, such asacetone or isopropanol, is again gradually added. The product obtainedafter the first or the second precipitation step is one of thehydrochloride salts of APIP, such as the monohydrochloride, thedihydrochloride or the dihydrochloride monohydrate.

According to a preferred embodiment of the invention 3-aminopiperidineis isolated from step c) as its dihydrochloride or dihydrochloridemonohydrate.

According to a particular preferred embodiment of the invention3-aminopiperidine, if it is obtained as its R- or S-enantiomer inenriched form, is isolated from step c) as its dihydrochloride or as itsdihydrochloride monohydrate.

In case the APIP obtained in step c) of the process A according to theinvention is racemic or of insufficient enantiomeric purity it may besubjected to enantiomeric enrichment in particular by fractionalcrystallization of APIP in the form of its acid-addition salt with achiral carboxylic acid of the formula A according to the second aspectof the invention.

According to the second aspect of the present invention, opticalresolution of the enantiomers of 3-aminopiperidine is achieved byfractional crystallization of the respective enantiomers in the form oftheir diastereomeric acid addition salts with a N-modified alaninederivative of the formula A as described above.

Therefore the invention also relates to a process for the enantiomericenrichment of APIP, which is herein also called process B. The processcomprises the fractional crystallization of APIP in the form of itsacid-addition salt with either a N-modified L-alanine derivative or aN-modified D-alanine derivative from a solution, emulsion or suspensioncontaining a mixture of the enantiomers of APIP, in particular a racemicmixture, and either the N-modified L-alanine derivative or theN-modified D-alanine derivative.

Suitable N-modified L-alanine derivatives are the L-alanine derivativesof the formula A-L while suitable N-modified D-alanine derivatives arethe D-alanine derivatives of the formula A-D, but are not limitedthereto:

wherein k is 0, 1, 2, 3, 4 or 5, R is CN, NO₂, C₁-C₂-alkyl, C₁-C₂-alkoxyor halogen, or two adjacent variables R may together represent anunsubstituted or substituted butan-1,3-dien-1,4-diyl, and X is S(O)₂,C(O) or NHC(O). In case the variable X is NHC(O) the nitrogen atom ofthe diradical NHC(O) is linked to the benzene ring. In formulae A, A-Land A-D the variables k, R and X, independently of each other, havepreferably the following meanings: The variable k is preferably 0, 1, 2or 3. X is preferably S(O)₂ or NHC(O). R is preferably C₁-C₂-alkyl,C₁-C₂-alkoxy or halogen.

The alanine derivatives of the formulae A-L and A-D are herein alsocalled chiral carboxylic acids A-L and A-D, respectively (herein alsonamed CAA).

Preferred herein are chiral carboxylic acids A-L and A-D wherein thevariable X is S(O)₂ or NHC(O), the variable k is 0 or 1 and the variableR is C₁-C₂-alkyl, in particular methyl, or halogen, in particular Cl.

According to preferred embodiment of the invention the chiral carboxylicacids A-L and A-D are of the formulae A-L or A-D, respectively, whereinX is S(O)₂, k is 0 or 1, and R, if present, is methyl or chloride andpreferably linked in the para position in relation to the variable X.These carboxylic acids A-L and A-D are herein also called carboxylicacids A-1-L and A-1-D, respectively.

Particular preferred carboxylic acids A-1-L are(S)-2-(4-methylphenyl)sulfonylamino-propionic acid (also known asN-(para-toluenesulfonyl)-L-alanine which is herein also named Ts-L-Ala),(S)-2-(4-chlorophenyl)sulfonylamino-propionic acid (also known asN-(para-chlorophenylsulfonyl)-L-alanine which is herein also namedpCl-Ps-L-Ala) and (S)-2-phenylsulfonylamino-propionic acid (also knownas N-(phenylsulfonyl)-L-phenylalanine which is herein also namedPs-L-Ala).

Particular preferred carboxylic acids A-1-D are(R)-2-(4-methylphenyl)sulfonylamino-propionic acid (also known asN-(para-toluenesulfonyl)-D-alanine which is herein also named Ts-D-Ala),(R)-2-(4-chlorophenyl)sulfonylamino-propionic acid (also known asN-(para-chlorophenylsulfonyl)-D-alanine which is herein also namedpCl-Ps-D-Ala) and (R)-2-phenylsulfonylamino-propionic acid (also knownas N-(phenylsulfonyl)-D-phenylalanine which is herein also namedPs-D-Ala).

According to another preferred embodiment of the invention the chiralcarboxylic acids A-L and A-D are of the formulae A-L or A-D, wherein Xis NHC(O), k is 0 or 1, and R, if present, is halogen, in particularchlorine, and preferably linked in the para position in relation to thevariable X. These carboxylic acids A-L and A-D are herein also calledcarboxylic acids A-2-L or A-2-D, respectively.

Particular preferred carboxylic acids A-2-L are(S)-2-(3-phenylureido)-propionic acid (also known asN-phenylcarbamoyl-L-alanine which is herein also named PC-L-Ala) and(S)-2-(3-(4-chlorophenyl)ureido)-propionic acid (also known asN-(4-chlorophenylcarbamoyl)-L-alanine which is herein also namedCl-PC-L-Ala).

Particular preferred carboxylic acids A-2-D are(R)-2-(3-phenylureido)-propionic acid (also knows asN-phenylcarbamoyl-D-alanine which is herein also named PC-D-Ala) and(R)-2-(3-(4-chlorophenyl)ureido)-propionic acid (also known asN-(4-chlorophenylcarbamoyl)-D-alanine which is herein also namedCl-PC-D-Ala).

It has been found that the R-enantiomer of APIP can be selectivelycrystallized from a mixture of APIP enantiomers by using the carboxylicacids A-1-L as N-modified L-alanine derivative in the inventive processB, while the S-enantiomer of APIP can be selectively crystallized from amixture of APIP enantiomers by using the carboxylic acids A-2-L.

It has also been found that the S-enantiomer of APIP can be selectivelycrystallized from a mixture of APIP enantiomers by using the carboxylicacids A-1-D as N-modified D-alanine derivative in the inventive processB, while the R-enantiomer of APIP can be selectively crystallized from amixture of APIP enantiomers by using the carboxylic acids A-2-D.

Thus, in a particular aspect the present invention provides a processfor obtaining the R-enantiomer of APIP, which comprises fractionalcrystallizing said R-enantiomer as its diastereomeric salt with acarboxylic acids A-1-L from a solution or suspension of a mixture of theenantiomers of APIP in at least one solvent.

Likewise, in another particular aspect the invention provides a processfor obtaining the S-enantiomer of APIP, which comprises fractionalcrystallizing said S-enantiomer as its diastereomeric salt with acarboxylic acids A-2-L from a solution or suspension of a mixture of theenantiomers of APIP in at least one solvent.

In a further particular aspect the present invention provides a processfor obtaining the S-enantiomer of APIP, which comprises fractionalcrystallizing said S-enantiomer as its diastereomeric salt with acarboxylic acids A-1-D from a solution or suspension of a mixture of theenantiomers of APIP in at least one solvent.

Yet, in a further particular aspect the invention provides a process forobtaining the R-enantiomer of APIP, which comprises fractionalcrystallizing said R-enantiomer as its diastereomeric salt with acarboxylic acids A-2-D from a solution or suspension of a mixture of theenantiomers of APIP in at least one solvent.

According to process B of the invention the acid addition salt of (R)-or (S)-APIP with a chiral carboxylic acid A-L or A-D (CAA) is typicallycrystallized from a suspension or a solution containing the mixture ofAPIP enantiomers suspended or dissolved, respectively, in d suitablesolvent or solvent mixture.

The mixture of the APIP enantiomers contained in the suspension or inthe solution may be a racemic mixture or a non-racemic mixture. If anon-racemic mixture is used, the excess of one enantiomer will generallynot exceed 30%, in particular 20%, i. e. the S/R-ratio (or R/S-ratio,respectively) will be in the range from 70:30 to 30:70, in particular inthe range from 60:40 to 40:60. Such non-racemic mixtures may be obtainedduring crystallization of one of the enantiomers from a solution of theracemic mixture of APIP or by addition of racemic APIP to a motherliquor from which one of the enantiomers had already been crystallized.Racemic mixtures as well as non-racemic mixtures can be used both in theprocess B according to the present invention.

The crystallization of the diastereomeric acid addition salt of APIPwith a CAA, in particular with those mentioned as preferred, in theprocess B of the invention can be performed by analogy to standardtechniques for the optical resolution of enantiomeric mixtures ofcompounds having a basic nitrogen atom with chiral acids, e.g. byanalogy to the methods described in the prior art cited in theintroductory part of the present application.

In particular, the crystallization of APIP is performed in the presenceof suitable amounts of the suitable CAA. Needless to say, the amount ofthe CAA is chosen to ensure crystallization of the diastereomeric acidaddition salt of APIP with the CAA. Usually, the amount of the CAA usedis at least 0.8 mol, in particular at least 0.9 mol per mol of thedesired APIP enantiomer (i.e. (S)-APIP or (R)-APIP, depending on whichenantiomer shall be crystallized) which is present in the solution orslurry before crystallization. Preferably, CAA is used in an amount of0.9 to 5 moles per mol of the desired APIP enantiomer which is containedin the solution or slurry before crystallization. Preferably, the CAA isused in an amount of 1.5 to 4.5 moles, in particular 1.8 to 4.2 moles,per mol of the desired APIP enantiomer which is contained in thesolution or slurry before crystallization, when the solution orsuspension contains a racemic mixture or a mixture of APIP enantiomers,wherein the relative amount of R- and S-enantiomer of APIP is close to1:1 (i.e. from 45:55 to 55:45).

The term “suitable CAA” means the CAA which is particularly suitable forcrystallizing the respective APIP enantiomer—i.e. in case of (R)-APIPthe suitable CAA is a carboxylic acid A-1, in particular those mentionedherein as preferred, while in case of (S)-APIP the suitable CAA is acarboxylic acids A-2, in particular those mentioned herein as preferred.

In order to achieve a high enantiomeric enrichment of the desired APIPenantiomer, the optical purity of the suitable CAA used in thecrystallization will generally be at least 70% ee, frequently at least80% ee, preferably at least 90% ee, in particular at least 95% ee andmore preferably at least 99% ee.

Preferably, the molar amount of CAA used in the process B according tothe present invention does not exceed more than 2.5 times the totalmolar amount of APIP present in the solution or suspension beforecrystallization. In particular, the CAA is used in an amount from 0.5 to2.5 moles, more preferably from 0.8 to 2.2 mol per mol of APIP which iscontained in the solution or suspension before crystallization.

In case the APIP is employed in process B in the form of one of itshydrochloride addition salts, such as the monohydrochloride or thedihydrochloride of APIP, said addition salts are generally transformedinto the free base prior to the crystallization according to well-knowntechniques. For this purpose the hydrochloride addition salts of APIPare usually treated with about 1 molar equivalents or about 2 molarequivalents of an aqueous base, depending on whether themonohydrochloride or the dihydrochloride of APIP is used. Suitableaqueous bases are aqueous solutions of ammonia, of a primary, secondaryor tertiary amine, such as methylamine, diethylamine, triethylamine,ethanolamine or triethanolamine, of an alkali metal carbonate, alkalimetal hydrogen carbonate or alkali metal hydroxide, such as sodiumcarbonate, potassium carbonate, sodium hydrogen carbonate, sodiumhydroxide. calcium hydroxide or potassium hydroxide. Preference is givento alkali metal hydroxide and in particular sodium hydroxide. It ispreferred to add the aqueous base in one portion or gradually to asolution of the hydrochloride addition salt of APIP in water or in oneof the mixtures of water with a water-miscible organic solvent describedbelow. The thus obtained mixture including the free base of APIP istypically directly subjected to the crystallization of process B withoutany preceding work-up steps. Alternatively, it is also possible totransform the hydrochloride addition salts of APIP Into the tree base bymeans of ion exchange resins.

For the crystallization according to process B of the present invention,CAA and the mixture of the APIP enantiomers is dissolved or suspended ina suitable solvent or solvent mixture. Preferably, CAA and the mixtureof APIP enantiomers are completely dissolved prior to crystallization.

The solution of CAA and the APIP enantiomers can be a homogeneoussolution, i. e. CAA, the mixture of enantiomers and at least one solventform a single phase prior to crystallization, or a heterogeneoussolution (multi-phase solution, such as an emulsion), wherein CAA andthe mixture of enantiomers are dissolved in at least one solvent or in amixture of at least two solvents of different polarity, thereby forminga multi-phase liquid. Both, the homogeneous solution and the emulsionmay further comprise solid material, in particular undissolved APIPenantiomers or undissolved CAA. Preferably, no undissolved APIP and noundissolved CAA are present prior to crystallization.

Suitable solvents include in particular water, polar organic solventsand mixtures thereof with water. Suitable organic solvents includeorganic solvents which are at least partially water-miscible, i.e. whichhave a miscibility with water of at least 20% (v/v) at 20° C., and alsosolvents which have a reduced miscibility with water, i.e. which have amiscibility with water of below 20% (v/v), in particular below 10% (v/v)at 20° C.,

Suitable organic solvents which are at least partially water-miscible,i.e. which have a miscibility with water of at least 20% (v/v) at 20°C., include, but are not limited to:

-   1. C₁-C₄-alkanols, such as methanol, ethanol, n-propanol or    isopropanol;-   2. C₁-C₄-carboxylic acids, such as formic acid, acetic acid or    propionic acid;-   3. amides, N-methylamides and N,N-dimethylamides of C₁-C₃-carboxylic    acids, such as formamide, dimethylformamide (DMF), acetamide and    N,N-dimethylacetamide;-   4. 5 or 6-membered lactames with a total of 7 carbon atoms, such as    pyrrolidone, N-methylpyrrolidone, N-ethylpyrrolidone,    N-isopropylpyrrolidone, N-hydroxyethylpyrrolidone;-   5. Dimethylsulfoxid and sulfolane;-   6. Ketones having 3 to 6 carbon atoms, such as acetone, 2-butanone,    2-pentanone, 3-pentanone, cyclopentanone and cyclohexanone;-   7. acetonitrile;-   8. 5- or 6-membered lactones, such as γ-butyrolactone;-   9. polyols and polyetherols, such as glycol, glycerin,    dimethoxyethan, ethylenglycolmonomethylether,    diethyleneglycoldimethylether, triethyleneglycol-dimethylether,    dipropyleneglycoldimethylether etc,-   10. Cyclic ethers, such as tetrahydrofurane, dioxane and trioxane,-   11. low molecular weight polyethyleneglycoles and low molecular    weight polypropyleneglycoles (MW≤400).

Suitable organic solvents which have a reduced miscibility with water,i.e. which have a miscibility with water of below 20% (v/v), inparticular at most 10% (v/v) at 20° C., include, but are not limited to:

-   12. aromatic solvents, such as benzene or its derivatives like    toluene, benzonitrile, nitrobenzene, chlorobenzene or xylene and    heteroaromatic liquids such as pyridine or furane;-   13. halogenated alkanes like dichloromethane, dichloroethane,    trichloroethane;-   14. dialkyl ethers having ≥4, e.g. 4 to 10 carbon atoms, such as    diethylether, tert.-butyl ethylether, diisopropylether or    tert-butylmethylether;-   15. esters of n-, i- or branched carboxylic acids with ≥5 carbon    atoms, including diesters, triesters, such as oils and fats, and    polyesters;-   16. alkanoles, aromatic and cyclic alcohols with ≥5, e.g. 5 to 10    carbon atoms, e.g. 2-hexanol, cyclohexanol, benzylalcohol or    octanol.

According to a preferred embodiment of the crystallization in theprocess B according to the present invention the solution of CAA and theAPIP enantiomers is a homogeneous solution.

Preferred solvents for the crystallization in process B comprise atleast one protic solvent, which is selected from water, C₁-C₄-alkanols,such as methanol, ethanol or isopropanol, and C₁-C₄-carboxylic acids,such as acetic acid. These solvents may be used as such, as a mixture orin a mixture with an aprotic solvent, in particular an aprotic solventhaving a reduced water solubility, e.g. an aprotic solvent having awater solubility of <20% (v/v), especially ≤10% (v/v) at 20° C.

In a very preferred embodiment of the crystallization of process B, thesolvent which is used for forming the solution or suspension compriseswater or at least one C₁-C₄-alkanol, such as preferably ethanol. Inparticular the solvent is water, a C₁-C₄-alkanol, such as in particularethanol, a mixture of 2, 3 or 4 and in particular 2 C₁-C₄-alkanols, suchas a mixture of ethanol and methanol, or a mixture of water with eithera C₁-C₄-alkanol or a C₁-C₄-carboxylic acid, such as in particular amixture of water with ethanol or with acetic acid.

In case the APIP is introduced into the crystallization according toprocess B in the form of its free base, the solvent used for forming thesolution or suspension is preferably selected from C₁-C₄-alkanol, suchas in particular ethanol, and mixtures of water with a C₁-C₄-alkanol,such as ethanol. In this context the ratio of water to C₁-C₄-alkanol inmixtures of water with a C₁-C₄-alkanol is the range from 20:80 (v/v) to80:20 (v/v), and in particular from 40:60 (v/v) to 60:40 (v/v).

In case the APIP is introduced into the crystallization according toprocess B in the form of one of its hydrochloride addition salts, thesolvent used for forming the solution or suspension is in preferablyselected from water and mixtures of water with a C₁-C₄-carboxylic acid,such as acetic acid. In this context the mixtures of water with aC₁-C₄-carboxylic acid consist of up to 10% by weight and preferably upto 5% by weight, such as 0.5 to 10% by weight, and in particular 1.5 to5% by weight, of the C₁-C₄-carboxylic acid.

In case an aqueous base is added to transform a hydrochloride additionsalt of APIP into its free base, as described above, the solventincluded in the volume of the aqueous base contributes to theaforementioned solvent used for forming a solution or suspension of CAAand APIP enantiomers in process B and therefore is also part of itstotal amount.

The crystallization of the diastereomeric acid addition salt of APIPwith CAA from the solution or suspension containing the mixture of APIPenantiomers may be achieved by conventional crystallization techniquesknow in the art. Usually, CAA and the mixture of the APIP enantiomers issuspended or preferably dissolved in a suitable solvent to obtain asuspension or preferably a solution of CAA and the APIP enantiomers insaid solvent.

The concentration of APIP in the suspension or solution is usually from1 to 20% by weight, in particular from 3 to 10% by weight and morepreferably from 3.5 to 5.5% by weight, based on the total amount ofsolvent and APIP in the form of its free base. The total amount of APIPand CAA will generally not exceed 40% by weight, in particular 25% byweight and more preferably 17% by weight, based on the total amount ofAPIP, CAA and solvent.

In order to sufficiently suspend or dissolve CAA and the APIPenantiomers it is usually advantageous to heat the solution orsuspension to a temperature of 30° C. to 150° C., preferably 40 to 120°C. and in particular 50 to 100° C. for a suitable period of time. Howsuch a solution of suspension of CAA and the APIP enantiomers in thesolvent is accomplished in detail is usually of secondary relevance.Thus, CAA and the APIP enantiomers may be added together to the solventwhich is then heated, or CAA may be added to a hot solution of the APIPenantiomers, to name only 2 of the possible options. The crystallizationis typically affected by cooling the solution or suspension totemperature of generally below 65° C., such as a temperature in therange of 10 to 65° C., preferably 15 to 45° C. and in particular 18 to42° C.

In order to assist the crystallization, it may be advantageous to dilutethe solution or suspension containing APIP and CAA with a solvent thatis miscible with the solvent used for preparing the solution orsuspension and in addition has a lower polarity. For instance,crystallization from a solution or suspension with a C₁-C₄-alkanol, e.g.ethanol, as sole or predominant solvent can favourably be initiated byadding another C₁-C₄-alkanol having a lower polarity, e.g. isopropanol.The amount of the less polar C₁-C₄-alkanol to be added to the solutionor suspension is preferably from 20 to 80% by weight, in particular 40to 60% by weight, relative to the amount of original solvent. Anotheroption to induce crystallization is to add seed crystals of theacid-addition salt of the desired APIP enantiomer with the suitable CAAto the solution or slurry containing APIP and CM. The amount of seedcrystals to be added to the solution or suspension is preferably from0.1 to 10 mmol, preferably from 0.2 to 8 mmol, in particular from 0.3 to5 mmol, per mol of the compound of APIP contained in the solution.

The thus formed acid addition salt of APIP with CAA is then separatedfrom the mother liquor by conventional separation techniques such asfiltration and centrifugation. The thus obtained crystalline material,after optionally washing it initially with the mother liquor, may bewashed with a suitable solvent, e. g. with water and/or a solvent inwhich the acid addition salt is only sparingly soluble or even insolubleto remove mother liquor and further impurities, in particular acidaddition salts of the non-desired APIP enantiomer. Preferably, afteroptionally washing with the mother liquor, the crystalline material issubjected to successive washes using solvents of declining polarity,e.g. after washing with water the crystals may be washed with aC₂-C₆-alkanol such as n-butanol or isobutanol, then with adi-C₁-C₄-alkyl ether such as diethyl ether, diisopropyl ether,tert-butylmethyl ether or tert-butylethyl ether and finally with a C₄-C₈alkane or C₅-C₈ cycloalkane such pentane, hexane or cyclohexane.

In the acid addition salt of APIP with CAA obtained by the process B ofthe present invention the molar ratio of the APIP enantiomers(hereinafter also referred to as S/R or R/S value) is usually at least90 to 10, corresponding to 80% ee, in particular at least 95:5,corresponding to 90% ee. However, optical purity can be further improvedby recrystallization of said acid addition salt from a suitable solvent.Suitable solvents include but are not limited to water, C₁-C₄-alkanols,in particular methanol or ethanol, and mixtures thereof with water. Bythis recrystallization, the optical purity can be improved to anenantiomeric excess of the desired enantiomer of at least 95% ee,preferably at least 98% ee or even at least 99%. In order to achieverecrystallization it is not necessary to completely dissolve the acidaddition salt. Likewise it is possible to stir a slurry of the salt in asuitable solvent for a prolonged period of time e.g. from 2 to 24 h,optionally applying a temperature gradient during stirring, startingwith a higher temperature and ending with a lower temperature.

Both the fractional crystallization of the acid additions salt of APIPwith CAA and the recrystallization of the acid additions salt of APIPwith CAA may be carried out as a batch process or as a continuousprocess. One means for carrying out the process continuously isillustrated in FIG. 1 of WO 97/32644, to which full reference is made.

The thus obtained acid addition salt of an APIP enantiomer with CAA maybe transformed into the free base according to well-known techniques,for example those described in the prior art cited in the introductorypart of the present application, such as treating the APIP/CAA acidaddition salt with diluted aqueous base and removing the CAA in itsanionic form for instance by means of ion exchange resins. Preferably,however, the acid addition salt of an APIP enantiomer with CAA isconverted into acid addition salt of the APIP enantiomer with a strongacid, such as hydrochloric acid. This is usually accomplished byinitially suspending the APIP/CAA addition salt in an aqueous solvent,such as water or a mixture of water with a water-miscible organicsolvent, and in particular water. The resulting suspension is treatedwith an aqueous solution of a strong mineral acid such as an aqueoushydrochloric acid or aqueous sulphuric acid, and in particularconcentrated aqueous hydrochloric acid (about 37% by weight). Thereby,the acid addition salt of enantiomeric APIP with the chiral carboxylicacids A is transferred into the acid addition salt of APIP with saidstrong mineral acid which remains dissolved in the aqueous phase, whilethe chiral carboxylic acid A precipitates from the aqueous phase. Theprecipitated chiral carboxylic acid A is recovered by filtration,washing and drying, and is then available for reuse. The mother liquoris washed with a suitable organic solvent of relative high polarity,such as some of the solvents listed in the group 6 mentioned before, inparticular 2-butanone, in order to remove traces of the chiralcarboxylic acid A. The mother liquor is then filtered, e.g. overdiatomaceous earth, and concentrated under reduced pressure and theobtained residue is optionally dried via one or two azeotropicdistillations under reduced pressure after adding for exampleisopropanol or a mixture of methanol and isopropanol. The finallyobtained product is the acid addition salt of an APIP enantiomer withsaid strong acid, and particular is a hydrochloride addition salt of anAPIP enantiomer, which may be further purified, e.g. byrecrystallization.

According to a preferred embodiment of the invention the acid additionsalt of an APIP enantiomer, in particular (R)-APIP, with CM is convertedinto enantiomeric APIP dihydrochloride monohydrate, in particular(R)-APIP dihydrochloride monohydrate, i.e. the addition salt of (R)- or(S)-APIP with hydrochloric acid which includes about 2 moles ofhydrochloric acid and about 1 mol of water per mol of APIP.

In contrast to the known anhydrous APIP dihydrochloride the (R)- as wellas (S)-APIP dihydrochloride monohydrate, and in particular (R)-APIPdihydrochloride monohydrate, have surprisingly been found to be highlycrystalline compounds which can easily be further purified, e.g. viacrystallization, in order to improve both their chemical andenantiomeric purity. (R)- and (S)-APIP dihydrochloride monohydratecrystallise in very large crystals generally >0.5 mm, (frequently a sizeof approx. 1-2 mm) that are easily filterable, have a very low tendencyfor hold-up of mother liquor and an increased stability and thereforefeature improved storage and handling properties compared to theanhydrous (S)- or (R)-APIP dihydrochloride (hereinafter also termed (S)-or (R)-APIP dihydrochloride anhydrate).

The present invention therefore also relates to crystalline(R)-3-aminopiperidine-dihydrochloride-monohydrate and(S)-3-aminopiperidine-dihydrochloride-monohydrate. Both (R)- and(S)-3-aminopiperidine-dihydrochloride-monohydrate comprise about 2moles, e.g. 1.90 to 2.10 moles and in particular 1.95 to 2.05 moles, ofhydrochloride and about 1 mol, e.g. 0.9 to 1.1 moles and in particular0.95 to 1.05 moles, of water.

Both (R)-3-am inopiperidine-dihydrochloride-monohydrate and(S)-3-aminopiperidine-dihydrochloride-monohydrate are characterized by aX-ray powder diffraction diagram, which, at 22° C. and using Cu-Kαradiation, displays at least 5, in particular at least 7, moreparticular at least 9 or at least 11, and especially all of thefollowing reflections, quoted as 2θ values: 11.0±0.2°, 16.4±0.2°,17.0±0.2°, 20.9±0.2°, 24.5±0.2°, 25.3±0.2°, 25.9±0.2°, 26.7±0.2°,27.3±0.2°, 28.4±0.2°, 29.3±0.2°, 30.0±0.2°, 30.7±0.2°, 31.0±0.2° and31.8±0.2°. Often at least one of the following reflections, inparticular 1, 2 or 3 of following reflections will be observed:17.0±0.2°, 20.9±0.2°, 24.5±0.2°, optionally together with 3 or more ofthe other reflections.

In contrast thereto, the known(R)-3-aminopiperidine-dihydrochloride-anhydrate and likewise the(R)-3-aminopiperidine-dihydrochloride-anhydrate are characterized by aX-ray powder diffraction diagram, which, at 22° C. and using Cu-Kαradiation, displays the following reflections, quoted as 2θ values:9.0±0.2°, 15.8±0.2°, 17.9±0.2°, 19.7±0.2°, 21.7±0.2°, 23.1±0.2°,24.4±0.2°, 25.3±0.2°, 28.9±0.2° and 30.7±0.2°.

(R)-3-aminopiperidine-dihydrochloride-monohydrate shows a specificrotation of >−1.5 in particular −1.7 (20° C., concentration C=10 in H₂Oand 589 nm), ee >98% (HPLC)

The water content in the(R)-3-aminopiperidine-dihydrochloride-monohydrate was determined to be9% (Karl-Fischer Titration). That corresponds to 1 mol of water per molof APIP.

In the NIR spectra (near infrared spectra) of the(R)-3-aminopiperidine-dihydrochloride-monohydrate the typical signals ofa hydrate are present, in particular a strong band at 5070 cm⁻¹. (seeFIG. 1)

The melting point for (R)-3-aminopiperidine-dihydrochloride-monohydrateis 204-207° C. That is almost identical to that of the anhydrous(R)-3-aminopiperidine-dihydrochloride as the water is removed duringheating.

As pointed out above, the diastereomeric acid addition salts of APIPwith CAA, in particular the acid addition salts of (R)-APIP with acarboxylic acids A-1 and the acid addition salts of (S)-APIP with acarboxylic acids A-2, are of high optical purity with regard to theenantiomers of APIP, the enantiomeric excess (% ee.) being generally atleast 70% ee, frequently 80% ee, preferably at least 90% ee, inparticular at least 95% ee, more preferably at least 98% ee or at least99% ee or at least 99.5% ee. These diastereomeric acid addition salts ofAPIP with CAA are novel and are also part of the invention.

In these salts the molar ratio of APIP to CAA is close to stoichiometry,but small deviations are possible. Usually the molar ratio of APIP toCAA in these salts is from 0.9:2 to 1.1:2, in particular from 0.95:2 to1.05:2.

The diastereomeric acid addition salts of APIP with CAA may be presentin pure form, i.e. the impurities different from APIP and CAA make up atmost 1% by weight, in particular at most 0.5% by weight or at most 0.1%by weight of the total weight of the acid addition salt. However, thediastereomeric acid addition salts of APIP with CAA may be present inthe form of solvates, e.g. hydrates, which are also part of the presentinvention. In particular, the diastereomeric acid addition salts of APIPwith CAA are present in the form of solvates with water. The solvatesmight be beneficial with regard to formation of crystalline material.Thus, a preferred embodiment of the invention relates to diastereomericacid addition salts of APIP with CAA in the form of solvates with water.According to a more preferred embodiment of the invention thediastereomeric acid addition salts of (R)-APIP with carboxylic acids A-1comprise about 1 mol, e.g. 0.95 to 1.05 moles and in particular 0.98 to1.02 moles, of water per mol of APIP, and the diastereomeric acidaddition salts of (S)-APIP with carboxylic acids A-2 comprise about 2moles, e.g. 1.90 to 2.10 moles and in particular 1.95 to 2.05 moles, ofwater per mol of APIP.

Thus, particularly preferred embodiments of the present invention relateto the following acid addition salts:

-   (R)-APIP (S)-2-(4-methylphenyl)sulfonylamino-hydropropionate (1:2)    monohydrate,-   (R)-APIP (S)-2-(4-chlorophenyl)sulfonylamino-hydropropionate (1:2)    monohydrate,-   (R)-APIP (S)-2-(phenyl)sulfonylamino-hydropropionate (1:2)    monohydrate,-   (S)-APIP (S)-2-(3-phenylureido)-hydropropionate (1:2) dihydrate, and-   (S)-APIP (S)-2-(3-(4-chlorophenyl)ureido)-hydropropionate (1:2)    dihydrate.

Those skilled in the art will appreciate that the invention describedherein is susceptible to variations and modifications other than thosespecifically described. The invention includes all such variation andmodifications. The invention also includes all of the steps, features,formulations and compounds referred to or indicated in thespecification, individually or collectively and any and all combinationsor any two or more of the steps or features.

The following examples shall serve the further illustration of theinvention and are not intended to limit the scope of the presentinvention

FIG. 1 shows the powder X-ray diffraction pattern of (R)-aminopiperidinedihydrochloride monohydrate obtained from example 5.

FIG. 2 shows the NIR spectrum of (R)-aminopiperidine dihydrochloridemonohydrate obtained from example 5.

FIG. 3 shows the IR spectrum of (R)-aminopiperidine dihydrochloridemonohydrate obtained from example 5.

FIG. 4 shows the powder X-ray diffraction pattern of (R)-aminopiperidinedihydrochloride anhydrate obtained from example 5.

ABBREVIATIONS

-   Ts-L-Ala: (S)-2-(4-methylphenyl)sulfonylamino-propionic acid-   pCl-Ps-L-Ala (S)-2-(4-chlorophenyl)sulfonylamino-propionic acid-   Ps-L-Ala: (S)-2-phenylsulfonylamino-propionic acid-   PC-L-Ala: (S)-2-(3-phenylureido)-propionic acid-   Cl-PC-L-Ala: (S)-2-(3-(4-chlorophenyl)ureido)-propionic acid-   rac-APIP: racemic 3-aminopiperidine-   (R)-APIP: (R)-3-aminopiperidine-   (3)-APIP. (S)-3-aminopiperidine-   S/R: enantiomeric ratio of (S)-APIP/(R)-APIP-   TBME: tert-butylmethyl ether-   MeOH: methanol-   MEK: methyl ethyl ketone (2-butanone)-   r.t.: room temperature (22° C.)-   conc.: concentrated

Analytics:

The enantiomeric ratio S/R was measured via chiral HPLC afterderivatisation with mosher's acid chloride on a Chiralpak AD 250/4.6/10column with hexane/isopropanol 90:10 as eluent. The detection wavelengthwas 220 nm. The retention times were: R_(t)(R-APIP)=0 min and R_(t)(S-APIP)=14 min, respectively.

Measurements of powder X-ray diffraction patterns were performed at roomtemperature (22° C.) on a powder diffractometer STOE STADI P usingCu-Kα₁ radiation (1.540598 Å) in Debeye Scherrer geometry. Samples werecontained in capillaries having an internal diameter of about 0.3 mm.

I Preparation of APIP Example 1: Preparation of Piperidine-3-CarboxylicAcid Hydrazide (Nipecotic Acid Hydrazide)

157 g racemic ethyl nipecotate and 53 g hydrazine hydrate were stirredovernight at 80° C. The solution was cooled to r.t, and graduallydiluted with 280 g TBME. The resulting suspension was stirred for onehour. Racemic nipecotic acid hydrazide (123 g) was isolated viafiltration under suction and drying at 50° C. as white crystallinesolid. Melting point: 111° C.

Example 2: Preparation of Piperidine-3-Carboxylic Acid Hydrazide(Nipecotic Acid Hydrazide) Monohydrochloride

157 g racemic ethyl nipecotate (technical grade, 1.0 mol) and 55.1 ghydrazine hydrate (1.1 mmol) were stirred overnight at 80° C. Thesolution was diluted with 100 g distilled water and cooled to r.t. Then99 g of conc. hydrochloric acid (1.0 mol) were slowly added, and thesuspension was stirred overnight. The precipitated crystals werefiltered and washed with cold water (2×10 ml), isopropanol (2×10 ml) andpentane (50 ml) to afford 119 g of racemic nipecotic acid hydrazidemonohydrochloride. Additional 25.4 g could be obtained from the motherliquor via evaporation and recrystallization from water. Thus, a totalof 144 g pure racemic nipecotic acid hydrazide monohydrochloride (80%)was isolated.

Melting point: 127° C.

Example 3: Preparation of (R)-APIP Dihydrochloride from R-EthylNipecotate Tartric Acid Salt

To a well stirred suspension of 153.6 g R-ethyl nipecotate L-tartaricacid salt in 157 g xylene (technical mixture) was added dropwise undercooling a solution of 69.3 g technical potassium hydroxide in 78 gwater. The organic phase was separated; the water phase was extractedagain respectively with 50 and 40 g xylene. The combined organic phasewas dried over 10 g sodium sulfate. The drying agent was filtered offand 39 g hydrazine hydrate was added. The biphasic mixture was heated to80° C. for 2 days under vigorous stirring. The mixture was concentratedunder vacuum and the residue was taken up in water and was concentratedagain to yield 168 g of a 40.6% solution of R-nipecotic acid hydrazidein water

To this solution was added 50 g of cracked ice. The pH was adjusted with77 g conc. hydrochloride acid to a value of 2.0. Approx. one fifth ofthis solution was set aside, and to the main part of the solution wasadded 1 ml conc. hydrochloride acid. Diazotation was carried out at <0°C. first with 18 g isopentyl nitrite, then the remaining nipecotic aciddhydrochloride solution, which had been put aside, was carefully addedunder cooling, and finally 53 g isopentyl nitrite were added dropwise ata temperature between −5 to −2° C. (about 200 g of cracked ice wereadded in portions to keep the mixture cold). Afterwards, the solutionwas stirred at 0° C. for one hour. The water phase was separated andpoured during 20 min onto 100 g of boiling water. Boiling was continuedfor 10 min, 5 g of conc. hydrochloride acid was added and the solutionwas concentrated to a final volume of 330 g with an APIP content of 66.2g (as dihydrochloride, yield is 76% over three steps) and a content ofthe side product nipecotic acid of 4.6 g. The solution was concentratedto a thick mass, which was taken up in 74 g of boiling methanol. Oncooling, R-APIP×2 HCl crystallized as thick mass. APIP×2 HCl wasisolated after dilution with 150 g acetone via filtration. After dryingin vacuo, 56.9 g dry R-APIP×2 HCl was obtained.

Example 4: Preparation of (R)-APIP Dihydrochloride with Hexyl Nitrite

To 68.3 g of a solution of R-nipecotic acid hydrazide in water (assay41.9%. 200 mmol) was added 70 g ice and 46.8 g conc. hydrochloric acid(475 mmol, 1.95 eq referring to the total amount of hydrazide). Theclear solution was cooled to −10° C., and 33 g n-hexyl nitrite was addedduring 30 min under cooling (ice/salt bath). 17.1 g of a solution ofR-nipecotic acid hydrazide in water (assay 41.9%. 50 mmol) was addedduring 10 min under cooling. Afterwards, additionally 16 g n-hexylnitrite was added during 20 min under cooling. The solution was stirredfor one hour at—−5° C., the water phase was separated and poured inportions onto 100 g of boiling water (>95° C.). The pH-value is now 1.9(measured via pH-paper). 5 g of conc. hydrochloric acid was added andthe solution was concentrated to a thick mass, which was taken up in 50g of boiling methanol. Isopropanol (100 g) was added, and the solutionwas concentrated to a mass of approx. 70 g. The solution was seeded, anddiluted with acetone (100 g). R-APIP×2 HCl (36 g, 83%) was isolated viafiltration and drying in vacuo.

Example 5: Preparation of (R)-APIP Dihydrochloride

To a solution of 136 kg (R)-nipecotic acid hydrazide in 194 kg deionizedwater was added 274 kg ice and 219 kg conc. hydrochloric acid. Thesolution was cooled to 0° C. and 60 kg isopentylnitrite was slowly addedat a temperature of −2 to +2° C. A solution of 14.6 kg (R)-nipecoticacid hydrazide in 18.4 kg water was added. The solution was cooled againto 0° C., and 117 kg isopentylnitrite was slowly added at a temperatureof −2 to +2° C. Finally the solution was stirred for 30 min at 0° C.This clear solution was pumped in small portions (about 30 l) to 400 kgwater at 90° C. After complete addition, the solution was heated at 90°C. for 30 min. The solution was cooled to r.t. and the phases wereseparated.

To three combined water phases obtained this way from a total of 544 kg(R)-nipecotic acid hydrazide was added 200 kg conc. hydrochloric acid.The solution was concentrated to a thick syrup and dissolved in hotmethanol (1300 kg). The solution was cooled to r.t., seeded with(R)-aminopiperidine dihydrochloride hydrate and diluted gradually with900 kg acetone. The resulting crystals of (R)-aminopiperidinedihydrochloride monohydrate were isolated via centrifugation (601 kgwet; water content: 9% (Karl-Fischer-Titration)).

The powder X-ray diffraction pattern of the sample is shown in FIG. 1.The characteristic reflections are quoted in the following table as 2θvalues or as interplanar spacings D together with relative intensities:

2θ D [Å] I rel [%] 11.0 8.1 20 16.4 5.4 34 17.0 5.2 73 20.9 4.2 100 24.53.6 92 25.3 3.5 32 25.9 3.4 44 26.7 3.3 48 27.3 3.3 20 28.4 3.1 42 29.33.0 27 30.0 3.0 31 30.7 2.9 36 31.0 2.9 53 31.8 2.8 29

The NIR-spectrum of (R)-aminopiperidine dihydrochloride monohydrate isshown in FIG. 2. The IR spectrum of (R)-aminopiperidine dihydrochloridemonohydrate is shown in FIG. 3.

To this solid was added methanol (400 kg) and isopropanol (1000 kg). Thesolvent was distilled under reduced pressure until a water content<1.0%was measured. The suspension was first diluted with methanol (400 kg)and then gradually with acetone (800 kg). The resulting solid wasisolated via centrifugation (563 kg wet) and dried at elevatedtemperatures under reduced pressure to afford 522 kg chemically pure(R)-aminopiperidine dihydrochloride in the form of its anhydrate with anoptical purity of >99ee.

The powder X-ray diffraction pattern of the sample is shown in FIG. 4.The characteristic reflections are quoted in the following table as 2θvalues or as interplanar spacings D together with relative intensities:

2θ D [Å] I rel [%] 9.0 9.8 30 15.8 5.6 27 17.9 4.9 70 19.7 4.5 75 21.74.1 39 23.1 3.8 64 24.4 3.6 100 25.3 3.5 78 28.9 3.1 95 30.7 2.9 49

Example 6: Preparation of Rac-APIP Dihydrochloride Hydrochloride withIsopentyl Nitrite

To 36 g (250 mmol) of racemic nipecotic acid hydrazide in 125 ml waterwere added 45 ml (500 mmol) of conc. hydrochloric acid under cooling(ice/salt). 25.1 g isopentyl nitrite (300 mmol) was added during 30 minat 0° C. and stirred at the same temperature for additional 30 min. HPLCshows complete conversion to the desired azide with no starting materialleft. The mixture was poured drop wise during 10 min onto 500 ml of hot(80° C.) water. Boiling was continued for additional 60 min. Thesolution was cooled to room temperature, conc. hydrochloric acid (40 ml)was added and the solution was concentrated to a viscous mass. Water(100 ml) was added, and the solution was concentrated again. Isopropylalcohol (100 ml) was added, and the solution was concentrated again. Theresidue was dissolved in hot methanol (50 ml). To the cooled methanolsolution was added acetone (100 g) dropwise under vigorous stirring.

The precipitated 3-aminopiperidine dihydrochloride was isolated (40 g ofwet product) and dried via azeotropic distillation under reducedpressure with two portions (50 ml each) of isopropanol. Hot methanol wasadded and the suspension was stirred over night at r.t. The suspensionwas diluted with TO g acetone and the solid material was isolated viafiltration. 33.2 g (192 mmol, corresponds to 77% yield) of3-aminopiperidine dihydrochloride was obtained as a white powder.Chemical purity (HPLC) is 98.7% with a water content (determined by KarlFischer titration) of 0.046%.

Example 7: Preparation of Rac-APIP Dihydrochloride with Acetic Acid asCosolvents

To 5.40 g of racemic nipecotic acid hydrazide dihydrochloride (25 mmol)in 10 g water and 2.5 g acetic acid were added dropwise 3.5 g isopentylnitrite (30 mmol) at −15° C. The clear solution was warmed to 0° C.during a period of 2 h and poured at once into 50 ml of boiling water.Boiling was continued for additional 10 min. The solution was cooled tor.t., conc. hydrochloride acid (2 ml) was added and the solution wasconcentrated to a viscous mass, which was dissolved in 10 ml of hotmethanol. On cooling the clear solution to r.t. a thick crystalline massdeveloped. Acetone (20 ml) was added and the crystals were isolated viafiltration. After drying for 12 h at 50° C., 3.71 g of racemic3-aminopiperidine dihydrochloride (21 mmol, corresponds to 84% yield)with a water content of 0.68% were obtained.

Example 8: Preparation of Rac-APIP Dihydrochloride with Isopropanol asCosolvents

To 5.40 g of racemic nipecotic acid hydrazide dihydrochloride (25 mmol)in 5 g water and 5 g isopropanol were added dropwise 3.5 g isopentylnitrite (30 mmol) at −15° C. The clear viscous solution was warmed to 0°C. during a period of 1 h and poured at once into 50 ml of boilingwater. Boiling was continued for additional 10 min. The solution wascooled to r.t., conc. hydrochloride acid (2 ml) was added and thesolution was concentrated to a viscous mass, which was dissolved in 10ml hot methanol. On cooling the clear solution to r.t. a thickcrystalline mass developed. Acetone (20 ml) was added and the crystalswere isolated via filtration. After drying for 12 h at 50° C., 3.42 g ofracemic 3-aminopiperidine dihydrochloride (20 mmol, corresponds to 80%yield) with a water content of 0.64% were obtained.

Example 9: Preparation of Racemic APIP Dihydrochloride with SodiumNitrite

18 g of racemic nipecotic acid hydrazide monohydrochloride (100 mmol)were dissolved in 36 g water and 21 g of 37% hydrochloric acid (210mmol) and cooled to −10° C. To the solution were added 7.6 g of NaNO₂(110 mmol) in small portions in such a way that the temperature is kept≤5° C. Stirring was continued for 30 min at a temperature of −5 to 0° C.The cold solution was then poured in small portions into 20 g of boilingwater. The reaction mixture was stirred under reflux for additional 30min and then cooled—to r.t. to give a solution of racemic APIPdihydrochloride in water.

II Enantiomeric Resolution of Racemic APIP by Fractional Crystallizationof Diastereomeric Acid Addition Salts Example 10: Resolution of Rac-APIPwith Ts-L-Ala

The solution of rac-APIP dihydrochloride obtained in Example 9 wasdiluted with 50 g distilled water, and then 100 ml of a 2N aqueoussolution of sodium hydroxide (200 mmol) were added dropwise on anice-water bath so that the pH-value is adjusted to 12. Afterwards 44 gof N-(para-toluenesulfonyl)-L-alanine (180 mmol) were added and thesuspension was heated to 90° C. for 30 min to afford a clear solution.This solution was then cooled to 60° C. The precipitated crystals wereaged at this temperature for 1 h and then stirred at r.t. overnight. Theobtained salt was collected by filtration, washed with 10 mlisopropanol, 2×10 ml pentane and dried to give 31.35 g of (R)-APIP.2Ts-L-Ala.H₂O as white solid. Yield: 52% (based on the amount of rac-APIPused).

Enantiomeric ratio S/R=9.57:90.43.

The obtained acid addition salt was purified by recrystallization from210 g of water,

Yield: 18.62 g, 31% (based on the amount of rac-APIP used).

Enantiomeric ratio S/R=0.2:99.8.

Example 11: Resolution of Rac-APIP with Ts-L-Ala

A solution of 400 mg (10 mmol) sodium hydroxide in 5.0 g water wereadded dropwise to a solution of 865 mg (5 mmol) rac-APIP dihydrochloridein 5.0 g water and the mixture was stirred for 10 min. 2428 mg (10 mmol)Ts-L-Ala were added and the mixture was heated at 80° C. until a clearsolutions was obtained. The solution was cooled slowly to r.t. and thesuspension was stirred for 3 h. The formed solid was collected byfiltration, washed with mother liquor, water, isobutanol, TBME andpentane (1 ml each) and dried to afford (R)-APIP.2 Ts-L-Ala.H₂O.

Yield: 1435 mg, 95% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=2.06:97.94; S-factor (efficiency of opticalresolution)=0.91.

The obtained acid addition salt was purified by recrystallization from13.0 g water.

Yield: 1087 mg, 72% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=0.0:100.0.

Melting point: 152° C.

Specific rotation [α]_(D) ²⁰=−3.8 (c=0.5. MeOH).

Example 12: Resolution of Rac-APIP with Ts-L-Ala

400 mg (10 mmol) sodium hydroxide in 5.0 g water and 300 mg (5 mmol)acetic acid were added subsequently to a suspension of 865 mg (5 mmol)rac-APIP dihydrochloride in 5.0 g water and stirred for 10 min. 1460 mg(6 mmol) Ts-L-Ala were added and the mixture was heated at 80° C. untila clear solution was obtained. The solution was cooled slowly to r.t.and the suspension was stirred for 3 h. The solid was collected byfiltration, washed with mother liquor, water, isobutanol, TBME andpentane (1 ml each) and dried to afford (R)-APIP.2 Ts-L-Ala.H₂O.

Yield: 1265 mg, 84% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=2.0:98.0.

The obtained acid addition salt was purified by recrystallization from12.0 g of water.

Yield: 858 mg, 57% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=0.0:100.0.

Example 13: Resolution of Rac-APIP with pCl-Ps-L-Ala

80 mg (2 mmol) sodium hydroxide in 1.0 g water were added dropwise to asolution of 173 mg (1 mmol) rac-APIP dihydrochloride in 1.0 g water andthe mixture was stirred for 10 min. 527 mg (2 mmol) pCl-Ps-L-Ala wasadded and the mixture was heated at 40° C. for 30 min. The solution wascooled slowly to r.t. and the suspension was stirred for 2 h. The formedsolid was collected by filtration, washed with mother liquor, water(2×0.5 ml), acetone (1 ml), and pentane (2 ml) and dried to afford(R)-APIP.2 pCl-Ps-L-Ala.H₂O.

Yield: 273 mg, 85% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=4.41:95.59; S-factor (efficiency of opticalresolution)=0.77.

A pure acid addition salt was independently prepared from 5 mmol(R)-APIP.2 HCl, 10 mmol NaOH and 10 mmol pCl-Ps-L-Ala in 10 g waterwhich had an optical purity of 100% and shows the following physicaldata:

Enantiomeric ratio S/R=0.0:100.0.

Melting point: 139° C.

Specific rotation [α]_(D) ²⁰=−0.3 (c=1.0, MeOH).

Example 14: Resolution of Rac-APIP with Ps-L-Ala

400 mg (10 mmol) sodium hydroxide in 5.0 g water were added dropwise toa solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g waterand the mixture was stirred for 10 min. 2293 mg (10 mmol) of Ps-L-Alawere added and the mixture was heated at 80° C. until a clear solutionswas obtained. The solution was cooled slowly to r.t. and the suspensionwas stirred for 3 h. The formed solid was collected by filtration,washed with mother liquor, water, isobutanol, TBME and pentane (1 mleach) and dried to afford (R)-APIP.2 Ps-L-Ala.H₂O as white solid.

Yield: 765 mg, 53% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=2.99:97.01.

Example 15: Resolution of Rac-APIP with Ps-L-Ala

400 mg (10 mmol) sodium hydroxide in 5.0 g water and 300 mg (5 mmol)acetic acid were added dropwise to a solution of 865 mg (5 mmol)rac-APIP dihydrochloride in 5.0 g water and the mixture was stirred for10 min. 1146 mg (5 mmol) of Ps-L-Ala were added and the mixture washeated at 80° C. until a clear solutions was obtained. The solution wascooled slowly to r.t. and the suspension was stirred for 3 h. The formedsolid was collected by filtration, washed with mother liquor, water,isobutanol, TBME and pentane (1 ml each) and dried to afford (R)-APIP.2Ps-L-Ala.H₂O as white solid.

Yield: 1069 mg, 74% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=3.71:96.29.

The obtained acid addition salt was purified by recrystallization from6.0 g of water.

Yield: 605 mg, 42% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=0.03:99.97.

Melting point: 180.6° C.

Specific rotation [α]D²⁰=−4.4 (c=0.5, MeOH).

Example 16: Resolution of Rac-APIP with PC-L-Ala

400 mg (10 mmol) sodium hydroxide in 5.0 g water were added dropwise toa solution of 865 mg (5 mmol) rac-APIP dihydrochloride in 5.0 g waterand the mixture was stirred for 10 min. 2082 mg (10 mmol) of PC-L-Alawere added and the mixture was heated at 80° C. until a clear solutionwas obtained. The solution was cooled slowly to r.t. and the suspensionwas stirred for 3 h. The formed solid was collected by filtration,washed with mother liquor, water, isobutanol, TBME and pentane (1 mleach) and dried to afford (S)-APIP.2 PC L-Ala 2H₂O as white solid.

Yield: 1220 mg, 88% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=98.88:1.12. S-factor (efficiency of opticalresolution)=0.86.

1000 mg of the obtained acid addition salt was purified byrecrystallization from 6.0 g of water.

Yield: 604 mg.

Enantiomeric ratio S/R=99.93:0.07.

Melting point: 135.2° C.

Specific rotation [α]_(D) ²⁰=+3.4 (c=0.5, MeOH).

Example 17: Resolution of Rac-APIP with Cl-PC-L-Ala

A mixture of 100 mg (1 mmol) rac-APIP and 246 mg (1 mmol)(S)-2-(3-(4-chlorophenyl)ureido)-propionic acid in 1000 mg ethanol washomogenized at 70° C., cooled down to r.t., diluted with 1 mlisopropanol and stirred for 1 h. The solids were filtered off, washedwith mother liquor, isopropanol, TBME and pentane (1 ml each) and driedto afford (S)-APIP.2 Cl-PC-L-Ala.2H₂O.

Yield: 209 mg, 67% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=96.74:3.26.

Example 18: Resolution of Rac-APIP with Cl-PC-L-Ala

A mixture of 350 mg (3.5 mmol) rac-APIP and 1723 mg (7 mmol(S)-2-(3-(4-chlorophenyl)ureido)-propionic acid in 7000 mg of aqueousethanol (50% (v/v)) was homogenized at 70° C. and cooled down to 40° C.thereby obtaining a precipitation. The suspension was stirred at thistemperature for 1 h and then at r.t. for another 1 h. The solid wascollected by filtration, washed with mother liquor, isopropanol, TBMEand pentane, (1 ml each) and dried to afford (S)-APIP.2L-p-Chlor-PC-Ala.2H₂O.

Yield: 1025 mg, 93% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=90.04:9.96.

The obtained acid addition salt was purified by stirring in 5.0 g ofaqueous ethanol (50% (v/v)) at 70° C., then at r.t.

Yield: 858 mg, 78% (based on the amount of enantiomer used).

Enantiomeric ratio S/R=99.7:0.3.

Melting point: 138°.

Specific rotation [α]_(D) ²⁰=+3.2 (c=0.5, MeOH)

III Conversion of Diastereomeric Acid Addition Salt of (R)-APIP with aChiral Acid into (R)-APIP Dihydrochloride Monohydrate ((R)-APIP.2HCl.H₂O) Example 19: Conversion of (R)-APIP.2 Ts-L-Ala.H₂O into(R)-APIP.2 HCl.H₂O

18.6 g (31 mmol) of (R)-APIP.2 Ts-L-Ala.H₂O (from Example 10) weresuspended in 80 g water, cooled with an ice-water bath and treated with15.3 g (155 mmol) conc. hydrochloric acid. The precipitated Ts-L-Ala wascollected by filtration, washed with 3×10 ml water and dried to obtain13.93 g (57 mmol; 92% yield) of recovered Ts-L-Ala. The mother liqueurwas washed with 2×50 ml MEK to remove last traces of Ts-L-Ala, filteredover celite and evaporated. The resulting yellow oil was dissolved in 20g methanol, diluted with 20 g isopropanol and evaporated to dryness.This procedure was repeated once again to afford 6.42 g(R)-APIP.2HCl.H₂O with an APIP (free base) content of 53.6% by weightand a water content of 4.2%. (Thus a mixture of the hydrate and theanhydrous APIP was obtained in this case).

Yield: 31% (based on the amount of racemate used).

Combined mother liqueurs from salt formation and purification wereevaporated to dryness and dissolved in 160 g of water. 27.6 g (280 mmol)conc. hydrochloric acid was added dropwise under ice cooling so that thepH-value is adjusted to 1. The solid was filtered off and dried toobtain 24.45 g (101 mmol) of recovered Ts-L-Ala. Total yield ofrecovered Ts-L-Ala: 38.38 g (158 mmol), 88% (based on the total amountused).

We claim:
 1. A process for preparing 3-aminopiperidine, which processcomprises the following steps: a) providing piperidine-3-carboxylic acidhydrazide, and b) transforming piperidine-3-carboxylic acid hydrazideinto piperidine-3-carbonyl azide by reacting piperidine-3-carboxylicacid hydrazide with a nitrite in the presence of an acid, and c)reacting piperidine-3-carbonyl azide in the presence of water and anacid, at a temperature in the range of 50 to 150° C., wherebypiperidine-3-carbonyl azide is converted into 3-aminopiperidine, wheresteps b) and c) are performed without isolation of piperidine-3-carbonylazide, and where in step c) the reaction mixture obtained after thecompletion of the conversion in step b) is added to a solvent whichcontains water and which has a temperature in the range of 50 to 150° C.2. The process of claim 1, where step a) comprises reacting aC₁-C₄-alkylester or benzylester of piperidine-3-carboxylic acid withhydrazine.
 3. The process of claim 2, wherein the C₁-C₄-alkylester ofpiperidine-3-carboxylic acid is ethyl ester of piperidine-3-carboxylicacid.
 4. The process of claim 1, where piperidine-3-carboxylic acidhydrazide is provided in a non-racemic mixture of its enantiomers, wherethe mixture is enantiomerically enriched with regard to one of itsenantiomers.
 5. The process of claim 4, where a C₁-C₄-alkylester ofpiperidine-3-carboxylic acid, which is enantiomerically enriched withregard to one of its enantiomers, is reacted with hydrazine to providethe piperidine-3-carboxylic acid hydrazide.
 6. The process of claim 5,wherein the C₁-C₄-alkylester of piperidine-3-carboxylic acid is ethylester of piperidine-3-carboxylic acid.
 7. The process of claim 5, wherestep a) comprises subjecting a racemic C₁-C₄-alkylester ofpiperidine-3-carboxylic acid, to enantiomeric enrichment with regard tothe R-enantiomer by fractional crystallization of an acid addition saltof the C₁-C₄-alkylester of piperidine-3-carboxylic acid with a chiralacid.
 8. The process of claim 7, wherein the C₁-C₄-alkylester ofpiperidine-3-carboxylic acid is ethyl ester of piperidine-3-carboxylicacid.
 9. The process of claim 7, where the chiral acid is tartaric acidor mandelic acid.
 10. The process of claim 9, wherein the chiral acid isL-tartaric acid or D-mandelic acid.
 11. The process of claim 1, wherestep b) comprises reacting piperidine-3-carboxylic acid hydrazide withan organic nitrite, in the presence of an acid.
 12. The process of claim1, where 3-aminopiperidine is isolated from step c) as itsdihydrochloride or dihydrochloride mono-hydrate.
 13. The process ofclaim 1, where the transformation in step b) is carried out in a solventselected from water, polar organic solvents and mixtures thereof toprovide a solution or dispersion of piperidine-3-carbonyl azide.
 14. Theprocess of claim 1, where the reaction mixture obtained after thecompletion of the conversion in step b) is introduced directly to theconversion in step c).
 15. The process of claim 1, wherein thewater-containing solvent is water, or mixtures of water with polarorganic solvents.